Orally disintegrable tablets

ABSTRACT

An orally disintegrable tablet, of the present invention, which comprises (i) fine granules having an average particle diameter of 400 μm or less, which fine granules comprise a composition coated by an enteric coating layer, said composition having 10 weight % or more of an acid-labile physiologically active substance and (ii) an additive, has superior disintegrability or dissolution in the oral cavity so that it can be used for treatment or prevention of various diseases, as an orally disintegrable tablet capable of being administered to the aged or children and easily administered without water. Also, because the tablet of the present invention contains fine granules having the average particle diameter such that it will not impart roughness in mouth, it can be administered easily without discomfort at the administration.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of application Ser. No. 12/151,572,filed May 7, 2008, which is a Continuation of Ser. No. 10/017,755, filedOct. 30, 2001, now issued U.S. Pat. No. 7,431,942, which is aContinuation of application Ser. No. 09/355,781, filed Aug. 4, 1999, nowissued U.S. Pat. No. 6,328,994, which is a U.S. National Stage ofApplication No. PCT/JP99/02548, filed May 17, 1999 which application isincorporated herein by reference.

TECHNICAL FIELD

The present invention relates to an orally disintegrable tablet having acharacteristic of fast disintegration in the oral cavity even withoutwater.

BACKGROUND ART

Pharmaceutical solid preparations, for example, tablets, usually areprepared to make pharmaceutically active ingredients absorb in adigestive organ by disintegration or dissolution through oraladministration, without fast disintegration or dissolution in the oralcavity.

JP-A-6-502194 (U.S. Pat. No. 5,464,632) discloses a rapidlydisintegrable multiparticulate tablet, the excipient mixture of which issuitable for imparting a disintegration rate such that the tabletdisintegrates in the mouth in less than sixty seconds, characterized bythe fact that the active substance is present in the form of coatedmicrocrystals or coated or uncoated microgranules. However, there is nodisclosure of an acid-labile physiologically active substance with abasic inorganic salt as the active substance, weight percentage of theactive substance in the excipient mixture, or the size of the coatedmicrogranule.

On the other hand, JP-A-5-92918 discloses a powder consisting of afine-particle core coated with a water-soluble high molecular compoundand at least one physiologically active substance, and having a granulesize of practically up to 500 μm. However, there is no disclosure of anacid-labile physiologically active substance with a basic inorganic saltas the physiologically active substance, weight percentage of the activesubstance in the coated granule or the size of the coated granule.

JP-A-63-301816 and U.S. Pat. No. 5,026,560 disclose spherical granuleshaving a core coated with spraying powder containing a drug and lowsubstituted hydroxypropylcellulose. However, there is no disclosure oforally disintegrable tablet.

EP-A-0452862 discloses a spherical granule obtained by coating apharmacologically inactive spherical seed core having at least 50 weight% microcrystalline cellulose and an average particle size of 100-1000μm, with a powder comprising an active ingredient, by using an aqueousbinding solution, and spraying an aqueous solution or suspension of acoating agent thereon. However, most of the particle sizes of thusobtained granules are 500 μm or more.

JP-A-1-268627, JP-A-1-268628 and JP-A-8-27033 disclose pharmaceuticalcompositions using erythritol, respectively.

However, there is no disclosure of solid pharmaceutical compositioncharacterized fast disintegration in the oral cavity.

JP-A-9-48726 discloses a buccal formulation consisting of a drug and asubstance wetting in a mouldable way on humidifying, and retaining ashape after moulding and drying.

As such substance, sugars, sugar alcohols and water-soluble polymers areexemplified.

JP-A-5-271054 discloses production of fast dissolving tablets comprisingan active ingredient and sugars.

JP-A-9-71523 discloses a tablet with rapid disintegration in the oralcavity comprising medicine, crystalline cellulose, low-substitutedhydroxypropyl cellulose and lubricant.

However, these prior art references nowhere disclose an acid-labilephysiologically active substance with a basic inorganic salt as anactive substance, weight percentage of the active substance in thetablet or the size of the coated fine granule.

To accompany an aging population and their changes in life environment,it is desired to develop an orally disintegrable solid preparationcapable of being administered without water, retaining the conveniencefor use which is a characteristic of a tablet, and being administered ondemand easily, anytime and anywhere, without water.

Conventional granules have large particle diameters, which results ininferior workability when dispensing, and also results in difficultiesin consistently adding a regular amount of the granules when they arecombined into tablets or capsules. Granules having a large particlediameter (400 μm or more of average particle diameter) also produce afeeling of roughness in the mouth. Accordingly, especially when used inan orally disintegrable tablet, the average particle diameter of theincluded granules must be about 400 μm or less, preferably about 350 μm.

For many reasons, such as, masking a bitter taste, or providing entericabilities or release abilities, it is desirable to prepare the solidpharmaceutical preparations as granules (or fine granules). Inparticular, in case of granules or fine granules in which the activeingredient of the drug is enteric coated to impart enteric dissolution,there is a need for enteric coating to prevent dissolution by stomachacid (i.e., to make the preparation acid-resistance). It is necessary tocoat the whole surface of the particle-before the entericcoating—(including a case of the crystal of physiologically activesubstance only, and a case of the granule produced by granulation), withthe enteric coating.

Namely, at least some uniform thickness (at least 20 μm or more) of thecoating layer is needed. Even a portion of thin and weak coating, isundesirable because acid-resistance is lowered. Accordingly, before theenteric coating, it is necessary that the particle is as spherical withsmooth surface as possible in form, as uniform as possible in size, andhas less cavity.

It is very difficult to produce an enteric coated fine granule with anaverage particle diameter of 400 μm or less, when the coating isperformed so that at least 20 μm thickness of coating layer may coat thewhole particle, and the enteric coated particle contains a basicinorganic salt for stabilization of an acid-labile physiologicallyactive substance, and where it contains binders for maintaining thestrength of the particle and/or disintegrants for maintaining thedisintegrability (dissolution) of the particles. Further, in the casewhere the content of the acid-labile physiologically active substance isincreased, it is necessary to also increase the content of theexcipients such as basic inorganic salt, binders and disintegrants.Furthermore, it is very difficult to produce a small enteric coated finegranule containing the physiologically active substance in high content.

Accordingly, it is desired to develop a fine granule which is coatedwith the enteric coating layer on the composition containing thephysiologically active substance such as a physiologically activesubstance containing a basic inorganic salt and which has a particlediameter so that roughness or oral discomfort is not felt, to develop afine granule containing the physiologically active substance, i.e., theactive ingredients of drugs, and so forth, in high content, to develop afine granule keeping enteric dissolution, a disintegrability anddissolution and suitable strength, and to develop an orallydisintegrable preparation containing such a fine granule, being a fastdisintegration type, showing superior oral disintegrability anddissolution and having suitable strength (hardness) so that it will notbe damaged through production processes or handling.

In particular, there is a need to combine an acid-labile physiologicallyactive substance, with basic inorganic salts and so forth for stability,and further to coat with coating layers such as an enteric layer. Insuch cases, it is an important problem to produce an small entericcoated fine granule, even though it contains the acid-labilephysiologically active substance in high concentration and in highcontent.

DISCLOSURE OF INVENTION

The present invention relates to:

[1] an orally disintegrable tablet which comprises (i) fine granuleshaving an average particle diameter of 400 μm or less, which finegranules comprise a composition coated by an enteric coating layer, saidcomposition having 10 weight or more of an acid-labile physiologicallyactive substance and (ii) an additive;

[2] an orally disintegrable tablet of the above [1], wherein the averageparticle diameter of the fine granules is 300 to 400 μm;

[3] an orally disintegrable tablet of the above [1], wherein the finegranules further comprise a basic inorganic salt;

[4] an orally disintegrable tablet of the above [1], wherein theadditive comprises a water-soluble sugar alcohol;

[5] an orally disintegrable tablet of the above [1], wherein thecomposition coated by an enteric coating layer is further coated by acoating layer which comprises a water-soluble sugar alcohol;

[6] an orally disintegrable tablet of the above [4], wherein theadditive comprises (i) crystalline cellulose and/or (ii) low-substitutedhydroxypropyl cellulose;

[7] an orally disintegrable tablet of the above [1], wherein theparticle diameter of the fine granules is practically 425 μm or less;

[8] an orally disintegrable tablet of the above [1], wherein theparticle diameter of the fine granules is practically 400 μm or less;

[9] an orally disintegrable tablet of the above [1], wherein theacid-labile physiologically active substance is a benzimidazole compoundor a salt thereof;

[10] an orally disintegrable tablet of the above [9], wherein thebenzimidazole compound is lansoprazole;

[11] an orally disintegrable tablet of the above [3], wherein the basicinorganic salt is a salt of magnesium and/or a salt of calcium;

[12] an orally disintegrable tablet of the above [1], wherein thecomposition comprises a core being coated by a benzimidazole compoundand a basic inorganic salt, said core comprising crystalline celluloseand lactose;

[13] an orally disintegrable tablet of the above [12], wherein the corecomprises 50 weight % or more of lactose;

[14] an orally disintegrable tablet of the above [12], wherein the corecomprises 40 to 50 weight % of crystalline cellulose and 50 to 60 weight% of lactose;

[15] an orally disintegrable tablet of the above [1], wherein thecomposition comprises 20 weight % or more of an acid-labilephysiologically active substance;

[16] an orally disintegrable tablet of the above [1], wherein thecomposition comprises 20 to 50 weight % of an acid-labilephysiologically active substance;

[17] an orally disintegrable tablet of the above [1], wherein the finegranules are produced by fluidized-bed granulation method;

[18] an orally disintegrable tablet of the above [1], wherein theenteric coating layer comprises an aqueous enteric polymer agent;

[19] an orally disintegrable tablet of the above [18], wherein theaqueous enteric polymer agent is a methacrylate copolymer;

[20] an orally disintegrable tablet of the above [18], wherein theenteric coating layer further comprises a sustained-release agent;

[21] an orally disintegrable tablet of the above [20], wherein thesustained-release agent is a methacrylate copolymer;

[22] an orally disintegrable tablet of the above [20], wherein thesustained-release agent is in an amount of 5 to 15 weight % relative to100 weight % of the aqueous enteric polymer agent;

[23] an orally disintegrable tablet of the above [4], wherein thewater-soluble sugar alcohol is erythritol;

[24] an orally disintegrable tablet of the above [4], wherein thewater-soluble sugar alcohol is mannitol;

[25] an orally disintegrable tablet of the above [5], wherein thewater-soluble sugar alcohol is in an amount of 5 to 97 weight relativeto 100 weight % of the orally disintegrable tablet apart from the finegranules;

[26] an orally disintegrable tablet of the above [4], wherein thecrystalline cellulose is in an amount of 3 to 50 weight % relative to100 weight % of the tablet apart from the fine granule;

[27] an orally disintegrable tablet of the above [6], wherein thecontent of hydroxypropoxyl group in the low-substituted hydroxypropylcellulose is 7.0 to 9.9 weight %;

[28] an orally disintegrable tablet of the above [6], wherein thecontent of hydroxypropoxyl group in the low-substituted hydroxypropylcellulose is 5.0 to 7.0 weight %;

[29] an orally disintegrable tablet of the above [1], which furthercomprises crospovidone;

[30] an orally disintegrable tablet of the above [1], wherein the oraldisintegration time is one minute or less;

[31] an orally disintegrable tablet of the above [1], which comprises nolubricant inside the tablet;

[32] fine granules having an average particle diameter of 400 μm orless, which comprise a composition coated by an enteric coating layer,said composition having (i) 25 weight % or more of an acid-labilephysiologically active substance and (ii) a basic inorganic salt;

[33] fine granules of the above [32], wherein the average particlediameter of the fine granules is 300 to 400 μm;

[34] fine granules of the above [32], wherein the particle diameter ofthe fine granules is practically 425 μm or less;

[35] fine granules of the above [32], wherein the particle diameter ofthe fine granules is practically 400 μm or less;

[36] fine granules of the above [32], wherein the acid-labilephysiologically active substance is a benzimidazole compound or a saltthereof;

[37] fine granules of the above [36], wherein the benzimidazole compoundis lansoprazole;

[38] fine granules of the above [32], wherein the basic inorganic saltis a salt of magnesium and/or a salt of calcium;

[39] fine granules of the above [32], wherein the composition comprisesa core being coated by a benzimidazole compound and a basic inorganicsalt, said core comprising crystalline cellulose and lactose;

[40] fine granules of the above [39], wherein the core comprises 50weight % or more of lactose;

[41] fine granules of the above [32], wherein the composition comprises25 to 40 weight % of an acid-labile physiologically active substance;

[42] fine granules of the above [32], which are produced byfluidized-bed granulation method;

[43] fine granules of the above [32], wherein the enteric coating layercomprises an aqueous enteric polymer agent;

[44] fine granules of the above [43], wherein the aqueous entericpolymer agent is a methacrylate copolymer;

[45] fine granules of the above [43], wherein the enteric coating layerfurther comprise a sustained-release agent;

[46] fine granules of the above [45], wherein the sustained-releaseagent is a methacrylate copolymer;

[47] fine granules of the above [45], wherein the sustained-releaseagent is in an amount of 5 to 15 weight % relative to 100 weight % ofthe aqueous enteric polymer agent;

[48] fine granules of the above [32], wherein the enteric coating layeris in an amount of 50 to 70 weight relative to 100 weight % of the finegranules;

[49] a tablet, granule, fine granule, capsule, effervescent orsuspension preparation which comprises the fine granules of the above[32], and so forth.

In the present specification, “coating” means also partial coating andadhesion or adsorption in addition to coating the whole surface of anObject (e.g., core) which is to be coated.

“Spherical” means also forms having a curved surface such as formshaving elliptic cross sections, and forms in the shapes of eggplants anddrops in addition to spheres.

“Average particle diameter” means volume based distribution mediandiameter (median diameter: 50% particle diameter from cumulativedistribution), unless otherwise specified. It can be measured by, forexample, a laser diffraction particle distribution measurement method.Concretely exemplified is a method using Raser Diffraction Analyzer,type: HEROS RODOS [trade name; manufactured by Sympatec (Germany)].

“An orally disintegrable tablet” of the present invention comprises (i)fine granules having an average particle diameter of 400 μm or less,which fine granules comprise a composition coated by an enteric coatinglayer, said composition having 10 weight % or more of an acid-labilephysiologically active substance and (ii) an additive.

In the present, invention, “fine granules having an average particlediameter of 400 μm or less, which fine granules comprise a compositioncoated by an enteric coating layer, said composition having 10 weight %or more of an acid-labile physiologically active substance” have anaverage particle diameter of about 400 μm or less, in order thatroughness is not felt in the mouth. Preferably, the average particlediameter of the fine granules is 300 to 400 μm.

Aside from the average particle diameter of the above “fine granules”,regarding the maximum particle size, the particle diameter ispractically 425 μm or less, and preferably practically 400 μm or less.Preferably, the particle diameter is practically 300 to 425 μm, morepreferably 300 to 400

“Practically” as used in “the particle diameter is practically 425 μm orless” and “the particle diameter is practically 400 μm or less” meansthat the particles may include a small quantity (about 5 weight % orless) of particles whose particle diameter is out of above describedrange, to include the inevitably contaminant particles.

“An acid-labile physiologically active substance” includes a compoundbeing unstable in an acidic region and/or a compound inactivated by anacid, especially a pharmaceutical ingredient. Concretely mentioned arevitamins such as vitamin B₁₂, fursultiamine, folic acid, vitamin A,vitamin D, as well as a known benzimidazole compound having an antiulceractivity of the formula (I) below, or a salt thereof.

wherein ring A may be substituted; R¹, R³ and R⁴ are the same ordifferent and each is a hydrogen, an alkyl or an alkoxy;

R² is C₁₋₄ alkyl which may be substituted by a substituent (s) selectedfrom the group consisting of halogen, hydroxy and C₁₋₄ alkoxy; and n is0 or 1.

In the above formula (I), “substituent(s)” of the “substituted ring A”include, for example, halogen, C₁₋₁₀ alkyl which may be substituted,C₃₋₇ cycloalkyl which may be substituted, C₂₋₁₆ alkenyl which may besubstituted, C₁₋₁₀ alkoxy which may be substituted, cyano, carboxy, C₁₋₇alkoxycarbonyl, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl,carbamoyl-C₁₋₄ alkyl, hydroxy, hydroxy-C₁₋₇ alkyl, C₁₋₆ acyl,carbamoyloxy, nitro, C₂₋₆ acyloxy, C₆₋₁₂ aryl, C₆₋₁₂ aryloxy, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, etc.

The “substituent” of the above “C₁₋₁₀ alkyl which may be substituted”,“C₃₋₇ cycloalkyl which may be substituted”, or “C₂₋₁₆ alkenyl which maybe substituted” includes, for example, (1) halogen, (2) nitro, (3) aminowhich may be substituted by 1 or 2 of C₁₋₄ alkyl and C₁₋₄ acyl, etc.,(4) amidino, (5) guanidino, (6) carbamoyl, etc. The number of thesesubstituent is 1 to 3.

The “substituent” of the above “C₁₋₁₀ alkoxy which may be substituted”includes, for example, (1) halogen, (2) nitro, (3) amino which may besubstituted by 1 or 2 of C₁₋₄ alkyl and C₁₋₄ acyl, etc., (4) amidino,(5) guanidino, etc. The number of these substituent is 1 to 3.

The above “C₁₋₆ acyl” includes, for example, C₂₋₆ alkanoyl such asformyl, acetyl, propionyl, etc.

The above “C₁₋₄ acyl” includes, for example, formyl and C₂₋₄ alkanoylsuch as acetyl, propionyl, etc.

The above “C₂₋₆ acyloxy” includes, for example, C₂₋₆ alkanoyloxy such asacetyloxyl, etc.

The above “C₆₋₁₂ aryl” includes, for example, phenyl, naphthyl, etc.

The above “C₆₋₁₂ aryloxy” includes, for example, phenoxy, naphthyloxy,etc.

The “alkyl” for R¹, R³ or R⁴ includes, for example, a straight-chain orbranched C₁₋₁₀ alkyl such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Among others,preferred is a straight-chain or branched C₁₋₆ alkyl. More preferred isa straight-chain or branched C₁₋₃ alkyl.

The “alkoxy” for R¹, R³ or R⁴ includes, for example, C₁₋₁₀ alkoxy suchas methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy,heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy,etc. Among others, preferred is C₁₋₆ alkoxy. More preferred is C₁₋₃alkoxy.

The “C₁₋₄ alkyl” of the “C₁₋₄ alkyl which may be substituted by asubstituent(s) selected from the group consisting of halogen, hydroxyand C₁₋₄ alkoxy” for R² includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

The “C₁₋₄ alkoxy” of the above “C₁₋₄ alkyl which may be substituted by aC₁₋₄ alkoxy” includes, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

The number of the substituents which the “C₁₋₄ alkyl” has is preferably1 to 3.

Salts of the benzimidazole compound include pharmaceutically acceptablesalts such as alkali metal salts, e.g., sodium salts and potassiumsalts, alkaline earth metal salts e.g., calcium salts and magnesiumsalts, etc.

Such benzimidazole compounds having an antiulcer activity, or saltsthereof include, for example, a compound or a salt thereof disclosed inJP-A-52-62275, JP-A-54-141783, JP-A-57-53406, JP-A-58-135881,JP-A-58-192880, JP-A-59-181277, JP-A-61-50978, JP-A-62-116576,JP-A-62-277322, JP-A-62-258320, JP-A-62-258316, JP-A-64-6270,JP-A-64-79177, JP-A-5-59043, JP-A-62-111980, JP-A-5-117268, EP-A-166287,EP-A-519365, and so forth.

The “physiologically active substance” of the present inventionpreferably is a benzimidazole compound or a salt thereof such aslansoprazole, omeprazole, rabeprazole, pantoprazole, perprazole,leminoprazole, TU-199, etc. Preferred is lansoprazole and omeprazole,etc. More preferred is lansoprazole.

The amount of the “acid-labile physiologically active substance” in the“composition” is, for example, about 10 weight % or more, preferablyabout 20 weight or more, more preferably about 23 weight % or more,especially preferably about 25 weight % or more. Among others, preferredis 20 to 50 weight %.

In the “composition”, a basic inorganic salt is preferably incorporatedwith the acid-labile physiologically active substance.

The “basic inorganic salt” includes, for example, a basic inorganic saltof sodium, potassium, magnesium and/or calcium, preferably a basicinorganic salt of magnesium and/or calcium. Among others, preferred is abasic inorganic salt of magnesium.

The basic inorganic salt of sodium includes, for example, sodiumcarbonate, sodium hydrogencarbonate, etc.

The basic inorganic salt of potassium includes, for example, potassiumcarbonate, potassium hydrogencarbonate, etc.

The basic inorganic salt of magnesium includes, for example, heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide, magnesium metasilicate aluminate, magnesium silicate,magnesium aluminate, synthetic hydrotalcite [Mg₆Al₂(OH)₁₆.CO₃.4H₂O],aluminum magnesium hydroxide [2.5MgO.Al₂O₃.xH₂O], etc. Among others,preferred is heavy magnesium carbonate, magnesium carbonate, magnesiumoxide, magnesium hydroxide, etc.

The basic inorganic salt of calcium includes, for example, precipitatedcalcium carbonate, calcium hydroxide, etc.

The preferable examples of the “basic inorganic salt” include heavymagnesium carbonate, magnesium carbonate, magnesium oxide, magnesiumhydroxide, etc.

Such basic inorganic salt of magnesium or calcium, etc. has a basic pH(not less than 7) when it is in the form of a 1% aqueous solution orsuspension.

Two or more of these basic inorganic salts (preferably a basic inorganicsalt of magnesium, a basic inorganic salt of calcium, etc.) can be usedas a mixture in a given ratio.

The amount of the basic inorganic salt to be used is appropriatelyselected depending on the kind of the basic inorganic salt and is, forinstance, about 0.3 to 200 weight %, preferably about 1 to 100 weight %,more preferably about 10 to 50 weight %, especially preferably about 20to 40 weight % relative to the benzimidazole compound or a salt thereof.

The “composition” may contain water-soluble polymers, the followingbinders, lubricants, and excipients, etc. in common use aspharmaceutical materials. The amount of such water-soluble polymers,binders, lubricants, and excipients is selected from amounts commonlyemployed in the manufacture of preparations in general dosage forms.

The “water-soluble polymer” includes, for example, a water-solublepolymer which is soluble in ethanol (i.e., an ethanol-solublewater-soluble polymer) such as a cellulose derivative (e.g.,hydroxypropyl cellulose, which may be referred to as “HPC” hereinafter),poly(vinylpyrrolidone), etc.; a water-soluble polymer which is insolublein ethanol (i.e., an ethanol-insoluble water-soluble polymer) such as acellulose derivative (e.g., hydroxypropylmethyl cellulose, which may bereferred to as “HPMC” hereinafter, methyl cellulose, carboxymethylcellulose sodium, etc.), sodium polyacrylate, polyvinyl alcohol, sodiumalginate, and guar gum, etc.

When such water-soluble polymers are used, the dissolution of drugs(physiologically active substances) can be controlled by employing themin combination with the ethanol-soluble water-soluble polymer andethanol-insoluble water-soluble polymer or by employing them incombination with some water-soluble polymers having different viscosity.

In the present invention, the “water-soluble polymer” is preferably, acellulose derivative such as HPC, HPMC, and methyl cellulose, andpolyvinyl alcohol. More preferred is a cellulose derivative such as HPC,HPMC.

The “HPC” contains, for example, about 53.4 to 77.5 weight %, morepreferably about 60 to 70 weight %, of hydroxypropoxyl group. Theviscosity of 2 weight % aqueous solution of HPC at 20° C. is usuallyabout 1 to 150,000 cps (centipoise). As the above HPC, hydroxypropylcellulose defined in Japanese Pharmacopoeia may be employed.Hereinafter, all viscosity of HPC is a value of 2 weight % aqueoussolution at 20° C.,

The “HPMC” is a mixed ether which is connected by a methoxy group and ahydroxypropoxy group. The content of the methoxy group of HPMC is, forexample, about 19 to 30 weight 4. The content of the hydroxypropoxygroup is, for example, about 4 to 12 weight %. The viscosity of 2 weight% aqueous solution of HPMC at 20° C. is usually about 1 to 40,000centistokes. As such HPMC may be employed hydroxypropylmethyl cellulose2208 defined by Japanese Pharmacopoeia, hydroxypropylmethyl cellulose2906 defined by Japanese Pharmacopoeia, hydroxypropylmethyl cellulose2910 defined by Japanese Pharmacopoeia, and so forth. Hydroxypropylcellulose(s) may be employed alone or in admixture of two or morethereof.

The content of the water-soluble polymer such as HPC and/or HPMC isusually about 0.1 to 50 weight %, preferably about 1 to 30 weight %, asagainst the whole “composition” containing the physiologically activesubstance, in order to control the dissolution of the physiologicallyactive substance in the composition containing the physiologicallyactive substance and retain a high content of the physiologically activesubstance.

The above “enteric coating layer” which coats the “composition having 10weight % or more of an acid-labile physiologically active substance”includes, for example, an aqueous enteric polymer agent such ascellulose acetate phthalate (CAP), hydroxypropylmethyl cellulosephthalate (hereinafter, referred to as HP-55), hydroxymethyl celluloseacetate succinate, methacrylate copolymer [e.g., Eudragit L30D-55 etc.(trade name; manufactured by Rohm GmbH (Germany)), KollICoat MAE30DP(trade name; manufactured by BASF (Germany)), Polyquid PA-30 (tradename; manufactured by SanyoKasei (Japan)), etc.], carboxymethylcellulose, shellac, etc.; a sustained-release agent such as methacrylatecopolymer [e.g., Eudragit NE30D (trade name), Eudragit RL30D (tradename), Eudragit RS30D (trade name), etc.]; a water-soluble polymer;plasticizers such as triethyl citrate, polyethylene glycol,acetylatedmonoglyceride, triacetin, castor oil, etc. and mixturesthereof.

The “aqueous enteric polymer agent” is preferably a methacrylatecopolymer. The “sustained-release agent” is preferably a methacrylatecopolymer.

The “sustained-release agent” is used in an amount of 5 to 30 weight %,preferably 5 to 15 weight %, relative to 100 weight % of the “aqueousenteric polymer agent”. The “plasticizers” is used in an amount of 5 to30 weight % relative to 100 weight % of the “aqueous enteric polymeragent”.

The “additives” of the “orally disintegrable tablet which comprises (i)fine granules having an average particle diameter of 400 μm or less,which fine granules comprise a composition coated by an enteric coatinglayer, said composition having 10 weight % or more of an acid-labilephysiologically active substance and (ii) an additive” may be onescommonly employed as pharmaceutical materials. The amount of suchadditives to be used is selected from amounts commonly employed in themanufacture of preparations in general dosage forms.

The “additives” include, for example, a water-soluble sugar alcohol, acrystalline cellulose, a low-substituted hydroxypropyl cellulose, aswell as, binders, acids, foaming agents, artificial sweeteners,flavorants, lubricants, colorants, stabilizers, excipients,disintegrants, and so forth.

The “water-soluble sugar alcohol” means a water-soluble sugar alcoholwhich needs water in an amount of less than 30 ml when 1 g ofwater-soluble sugar alcohol is added to water and dissolved within about30 minutes at 20° C. by strongly shaking every 5 minutes for 30 seconds.

The “water-soluble sugar alcohol” includes, for example, sorbitol,mannitol, maltitol, reduced starch saccharide, xylitol, reducedparatinose, erythritol, etc. Two or more of these water-soluble sugaralcohols can be used as a mixture in a given ratio.

The “water-soluble sugar alcohol” is preferably mannitol, xylitol anderythritol. More preferred is mannitol and erythritol. Especiallypreferred is mannitol. As erythritol, one that is produced byfermentation with yeasts using glucose as the starting material, andthat has a particle size of at most 50 mesh is used. Such erythritol isavailable on the market, e.g. as manufactured by Nikken Chemical Co.,Ltd. (Japan).

The “water-soluble sugar alcohol” is usually employed in an amount ofabout 5 to 97 weight %, preferably about 10 to 90 weight % relative to100 weight % of the orally disintegrable tablet apart from the finegranules, in order to obtain sufficient strength of the preparation andsufficient disintegration or dissolution in the oral cavity.

For example, mannitol or erythritol is usually employed in an amount ofabout 5 to 90 weight %, preferably about 10 to 80 weight %, morepreferably about 20 to 80 weight %, especially preferably about 50 to 80weight % relative to 100 weight % of the orally disintegrable tabletapart from the fine granules.

The “crystalline cellulose” includes refined one having partiallyα-cellulose depolymerization. Such crystalline cellulose includes onecalled microcrystalline cellulose. Examples of the “crystallinecellulose” include CEOLUS KG801, avicel PH101, avicel PH102, avicelPH301, avicel PH302, avicel RC-591 (crystalline cellulose carmellosesodium), etc. Among these, preferably employed is CEOLUS KG801 which isalso called crystalline cellulose of high compressibility. Two or moreof the crystalline cellulose can be used as a mixture in a given ratio.Such crystalline cellulose is available on the market, for example, asmanufactured by Asahi Chemical Co., Ltd. (Japan).

The “crystalline cellulose” is used, for instance, in an amount of about3 to 50 weight %, preferably about 5 to 40 weight %, more preferablyabout 5 to 20 weight % relative to 100 weight % of the orallydisintegrable tablet apart from the fine granules.

The “low-substituted hydroxypropyl cellulose” means a low-substitutedhydroxypropyl cellulose wherein the content of hydroxypropoxyl group inthe hydroxypropyl cellulose (hereinafter, may be abbreviated to “thecontent of HPC group”) is about 5.0 to 9.9 weight %, preferably alow-substituted hydroxypropyl cellulose wherein the content of HPC groupis about 5.0 to 7.0 weight %, a low-substituted hydroxypropyl cellulosewherein the content of HPC group is about 7.0 to 9.9 weight %, and soforth.

The “low-substituted hydroxypropyl cellulose wherein the content of HPCgroup is about 7.0 to 9.9% includes, for example, LH-22, LH-32 andmixtures thereof, which are commercially available [Shin-Etsu ChemicalCo., Ltd. (Japan)]. Also, they can be produced in accordance with per seknown methods, for example, methods described in JP-B-82 53100 oranalogous thereto.

The low-substituted hydroxypropyl cellulose wherein the content of HPCgroup is about 5.0 to 7.0% includes, for example, LH-23, LH-33 andmixtures thereof, described in the following Reference Examples. Theycan be produced in accordance with per se known methods, for example,methods described in JP-B-82 53100 or analogous thereto.

At first, alkaline cellulose containing free alkaline and propyleneoxide is reacted to obtain the crude low-substituted hydroxypropylcellulose containing free alkaline.

Concretely, for example, raw material pulp such as wood pulp and cottonleader is immersed in about 10 to 50% concentration of an aqueoussolution of sodium hydroxide, and pressed to obtain alkaline celluloseof which NaOH/cellulose ratio is about 0.1 to 1.2 (ratio by weight).Next, crude low-substituted hydroxypropyl cellulose containing freealkaline is obtained by reacting the resulting alkaline cellulose andpropylene oxide with stirring at about 20 to 90° C. for about 2 to 8hours. Propylene oxide is used in an amount so that the content ofhydroxypropoxyl group in the desired low-substituted hydroxypropylcellulose can be 5 or more weight % to less than 7 weight % (in case ofthe low-substituted hydroxypropyl cellulose wherein the content of HPCgroup is about 5.0 to 7.0 weight %), 7 or more weight % to less than 9.9weight % (in case of the low-substituted hydroxypropyl cellulose whereinthe content of HPC group is about 7.0 to 9.9 weight %).

The crude low-substituted hydroxypropyl cellulose containing freealkaline is dispersed in water or hot water containing about 5 to 80% ofacid necessary to neutralize all the alkaline, and a part of the crudelow-substituted hydroxypropyl cellulose containing free alkaline isdissolved therein. Acid is further added to neutralize the remainingalkaline.

After the neutralization, some processes such as drainage, drying andgrinding are performed in accordance with conventional methods to obtainthe desired low-substituted hydroxypropyl cellulose.

The particle diameter of “the low-substituted hydroxypropyl celluloseswherein the content of hydroxypropoxyl group is 5.0 to 7.0 weight %” tobe used in the present invention is, for example, about 5 to 60 μm,preferably about 10 to 40 μm, as a average particle diameter.

In the above ranges, in case that low-substituted hydroxypropylcelluloses (L-HPC) having a relatively large particle diameter (forexample, L-HPC having about 26 to 40 μm of the average particlediameter) is employed, a pharmaceutical preparation superior indisintegrability can be produced. On the other hand, in case that L-HPChaving a relatively small particle diameter (for example, L-HPC havingabout 10 to 25 μm of the average particle diameter) is employed, apharmaceutical preparation superior in strength of the preparation canbe produced. Accordingly, the particle diameter of L-HPC can be suitablyselected according to the characteristics of the desired pharmaceuticalpreparation.

The “low-substituted hydroxypropyl cellulose wherein the content of HPCgroup is 5.0 to 7.0 weight %” or the “low-substituted hydroxypropylcellulose wherein the content of HPC group is 7.0 to 9.9%” is usuallyemployed in an amount of about 3 to 50 weight %, preferably about 5 to40 weight %, relative to 100 weight % of the orally disintegrable tabletapart from the fine granules, in order to obtain sufficient oraldisintegrability and sufficient strength of the preparation.

The “binders” include, for example, hydroxypropyl cellulose,hydroxypropylmethylcellulose, crystalline cellulose, a starch(pregelatinized starch), polyvinylpyrrolidone, gum arabic, powder,gelatin, pullulan, low-substituted hydroxypropyl cellulose, etc. The useof crystalline cellulose as the binders provides a solid preparationwhich exhibits more excellent strength of a preparation while retainingexcellent disintegration and dissolution in the oral cavity.

The “acids” include, for example, citric acid (e.g., citric acidanhydrous), tartaric acid, malic acid, etc.

The “foaming agents” include, for example, sodium hydrogen carbonate,etc.

The “artificial sweeteners” include, for example, saccharin sodium,dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, etc.

The “flavorants” include synthetic flavorants or natural flavorants,such as lemon, lime, orange, menthol, strawberry, etc.

The “lubricants” include, for example, magnesium stearate, sucrose fattyacid ester, polyethyleneglycol, talc, stearic acid, etc.

The “colorants” include, for example, various food colorants such asFood Yellow No. 5, Food RED No. 2, Food Blue No. 2, etc., food lakes,red iron oxide, etc.

The “stabilizers” include, for example, the above-mentioned “basicinorganic salt”.

The “excipients” include, for example, lactose, sucrose, D-mannitol,starch, corn starch, crystalline cellulose, light silicic anhydride,titanium oxide, etc.

The “disintegrants” include those conventionally used in thepharmaceutical field, such as (1) crospovidone, (2) super disintegrantssuch as croscarmellose sodium [FMC-Asahi Chemical Co., Ltd. (Japan)],carmellose calcium [Gotoku Chemical (Yakuhin), (Japan)], (3)carboxymethylstarch sodium [e.g., Matsutani Chemical Co., Ltd. (Japan)],(4) low-substituted hydroxypropyl cellulose [e.g., Shin-Etsu ChemicalCo., Ltd. (Japan)], (5) corn starch, etc. Among others, preferred is,for example, crospovidone.

The “crospovidone” includes polyvinylpolypyrrolidone (PVPP),1-vinyl-2-pyrrolidinone homopolymer, 1-ethenyl-2-pyrrolidinonehomopolymer, etc, such as Kollidon CL [manufactured by BASF (Germany)],Polyplasdone XL [manufactured by ISP Ltd. (Japan)], Polyplasdone XL-10[manufactured by ISP Ltd. (Japan)], Polyplasdone INF-10 [manufactured byISP Ltd. (Japan)], etc. Usually crospovidone having a molecular weightof at least 1,000,000 is used.

Two or more of these disintegrants can be as a mixture in a given ratio.For example, (i) crospovidone solely, or (ii) crospovidone and anotherdisintegrants) is preferably employed.

The “disintegrants” are used, for instance, in an amount of about 1 to15 weight %, preferably about 1 to 10 weight %, more preferably about 3to 7 weight %, relative to 100 weight % of the orally disintegrabletablet apart from the fine granules.

In the present invention, the “fine granules” may contain, for example,titanium oxide as a masking agent.

The diameter of the “orally disintegrable tablet” of the presentinvention is about 5 to 20 mm, preferably about 7 to 15 mm, morepreferably about 8 to 13 mm.

The “orally disintegrable tablet” may comprise no lubricant inside thetablet.

The “orally disintegrable tablet” of the present invention exhibits fastdisintegrability or dissolubility in the oral cavity, and also anappropriate strength of preparation.

The oral disintegration time of the “orally disintegrable tablet” of thepresent invention (the time for healthy male or female adults tocomplete disintegration by buccal saliva) is one minute or less, usuallyabout 50 seconds or less, preferably about 40 seconds or less, morepreferably about 30 seconds or less.

The strength of the “orally disintegrable tablet” of the presentinvention (measurement with a tablet hardness tester) is usually about 1to 20 kg, preferably about 2 to 15 kg, more preferably 3 to 8 kg.

In the above-mentioned fine granules, “fine granules having an averageparticle diameter of 400 μm or less, which comprise a composition coatedby an enteric coating layer, said composition having (i) 25 weight % ormore of an acid-labile physiologically active substance and (ii) a basicinorganic salt” are novel.

The “fine granules” have an average particle diameter of about 400 μm orless, preferably 350 μm or less. Preferably, the average particlediameter of the fine granules is 300 to 400 μm. Aside from the averageparticle diameter of the “fine granules”, regarding the maximum particlesize, the particle diameter is practically 425 μm or less, andpreferably practically 400 μm or less. Preferably, the particle diameteris practically 300 to 400 μm or less.

Regarding the fine granule of the present invention, the dissolution ofthe physiologically active substance can be controlled by formulatingthe coat (coating layer) to have different viscosity or content of thewater-soluble polymer (e.g., HPC, HPMC and so forth) or by formulatingthe coat to have a controlled ratio of the ethanol-soluble water-solublepolymer (e.g., HPC) and the ethanol-insoluble water-soluble polymer(e.g., HPMC). The dissolution of the physiologically active substance isnot very influenced by liquidity, which can be suitably controlled.

As a pharmaceutical preparation which comprises the “fine granules” ofthe present invention, there may be employed, for example a solidpreparation such as tablet, granule, fine granule, capsule,effervescent, etc; a liquid preparation such as suspension preparation,etc. Among others, preferred is a tablet, more preferred is an orallydisintegrable tablet.

When the “fine granule” of the present invention is used for a tabletexcept for an orally disintegrable tablet, the diameter of the tablet isabout 5 to 10 mm, preferably about 5 to 8 mm. When the fine granule ofthe present invention is used for a capsule, the size of the capsule ispreferably a #2 capsule or less.

The “orally disintegrable tablet” of the resent invention and the“pharmaceutical preparation which comprises the fine granules of thepresent invention” may contain a foaming component to impart arefreshing feeling at administration.

Also, with an effervescent comprising the foaming component, thedissolution can be precisely controlled compared to the case of a finegranule alone. As the foaming component, various compounds can beemployed as long as safety is not interfered with. Examples of thefoaming component include alkaline metal carbonate (e.g., sodiumcarbonate, potassium carbonate, etc.), alkaline metal hydrogencarbonate(e.g., sodium hydrogencarbonate, potassium hydrogencarbonate, etc.) andammonium carbonate and so forth. The foaming component(s) may beemployed alone or in an admixture of two or more thereof.

The preferable foaming component includes sodium carbonate, sodiumhydrogencarbonate, ammonium carbonate and so forth.

The ratio of the foaming component can be selected within the range inwhich it is possible to impart the foam, for example, about 10 to 2500weight %, preferably about 50 to 2000 weight % (e.g., about 75 to 1500weight %), more preferably about 100 to 1000 weight %, relative to 100weight % of the fine granule.

In employing the effervescent and the fine granule having small particlediameter, it is advantageous to quickly prepare a homogeneous aqueoussolution or suspension, and to maintain the dispersed condition. But, incase that the particle diameter is too small, the problem tends to occurthat the fine granule adheres to the wall of machine by staticelectricity during production processes.

The specific volume of the above fine granule is about 3 ml/g or less,preferably about 2 ml/g or less. In order to maintain the homogeneouscondition of the fine granule in the suspension obtained by adding thefoaming agent composition, the specific volume can be suitably selectedin the above range according to the specific gravity (specific volume)of the dispersion medium.

The “composition” in the present invention can be produced by a knowngranulation method.

The “granulation method” includes, for example, rolling granulationmethod (e.g., centrifugal rolling granulation, etc.), fluidized-bedgranulation (e.g., rolling fluidized-bed granulation, fluidizedgranulation, etc.), stirring granulation and so forth. Among others,preferred is fluidized-bed granulation method, more preferred is rollingfluidized-bed granulation method.

Concrete example of the “rolling granulation method” includes a methodusing “CF apparatus” manufactured by Freund Industrial Co., Ltd. (Japan)and so forth. Concrete examples of the “rolling fluidized-bedgranulation method” include methods using “SPIR-A-FLOW”, “multi plex”manufactured by Powrex Corp. (U.S.A.), “New-Marumerizer” manufactured byFuji Paudal Co., Ltd. (Japan), and so forth. The method for spraying themixture can be suitably selected in accordance with the kind ofgranulator, and may be, for example, any one of a top spray method, abottom spray method, a tangential spray method, and so forth. Amongothers, a tangential spray method is preferred.

The “composition” in the present invention can be produced in accordancewith, for example, a method which comprises coating a core comprisingcrystalline cellulose and lactose with an acid-labile physiologicallyactive substance.

For example, employed is a method described in JP-A-5-92918 (coatingmethod), which comprises coating a core comprising crystalline celluloseand lactose with an acid-labile physiologically active substance, ifnecessary together with a basic inorganic salt, binders, lubricants,excipients, a water-soluble polymer, etc. (hereinafter, may beabbreviated to “coating layer”). For example, employed is a method whichcomprises coating a core with an acid-labile physiologically activesubstance and a basic inorganic salt, and then further with binders,lubricants, excipients, a water-soluble polymer, etc.

The average particle diameter of the “cores” is about 250 μm or less,preferably about 50 to 250 μm, more preferably about 100 to 250 μm,especially preferably about 100 to 200 μm. The “cores” having the aboveaverage particle diameter include particles which all pass through a #50sieve (300 μm), particles where about 5 w/w % or less of the totalremain on a #60 sieve (250 μm), and particles where about 10 w/w % orless of the total pass through a #282 sieve (53 μm). The specific volumeof the “core” is about 5 ml/g or less, preferably about 3 ml/g or less.

Examples of the “core” include

(1) a spherical granulated product comprising crystalline cellulose andlactose, (2) a spherical granulated product being about 150 to 250 μmand comprising crystalline cellulose (avicel SP, manufactured by AsahiChemical Co., Ltd. (Japan)), (3) a stirring granulated product beingabout 50 to 250 μm and comprising lactose (9 parts) and a starch (1part), (4) a micro particle being about 250 μm or less classified as aspherical granule comprising micro crystalline cellulose described inJP-A-61-213201, (5) a processed product such as wax formed to a sphereby spraying or melting granulation, (6) a processed product such asgelatin beads comprising oil component, (7) calcium silicate, (8)starch, (9) a porous particle such as chitin, cellulose, chitosan, etc,and (10) a bulk product such as granulated sugar, crystalline lactose orsodium chloride, and processed preparations thereof. Further, thesecores may be produced in accordance with per se known grinding method orgranulation method, and sifted to prepare the particles having thedesired particle diameter.

The above “spherical granulated product comprising crystalline celluloseand lactose” includes, for example (i) a spherical granulated productbeing 100 to 200 μm and comprising crystalline cellulose (3 parts) andlactose (7 parts) [e.g., Nonpareil 105 (70-140) (particle diameter of100 to 200 μm), manufactured by Freund Industrial Co., Ltd. (Japan)],(ii) a spherical granulated product being about 150 to 250 μl andcomprising crystalline cellulose (3 parts) and lactose (7 parts) [e.g.,Nonpareil NP-7:3, manufactured by Freund Industrial Co., Ltd. (Japan)],(iii) a spherical granulated product being 100 to 200 μm and comprisingcrystalline cellulose (4.5 parts) and lactose (5.5 parts) [e.g.,Nonpareil 105T (70-140) (particle diameter of 100 to 200 μm),manufactured by Freund Industrial Co., Ltd. (Japan)], (iv) a sphericalgranulated product being about 150 to 250 μm and comprising crystallinecellulose (5 parts) and lactose (5 parts) [e.g., Nonpareil NP-5:5,manufactured by Freund Industrial Co., Ltd. (Japan)], and so forth.

In order to produce a pharmaceutical preparation which is superior indissolution while retaining suitable strength, the “core” includes, forexample, preferably the spherical granulated product comprisingcrystalline cellulose and lactose, more preferably the sphericalgranulated material comprising crystalline cellulose and lactose andcontaining 50 weight % or more of lactose. Among others, preferred is acore comprising 40 to 50 weight % of crystalline cellulose and 50 to 60weight % of lactose.

As the “core” employed in the present invention, in particular, theremay be employed the spherical granulated product comprising crystallinecellulose and lactose, more preferably the spherical granulated productwith a diameter of about 100 to 200 μm and comprising crystallinecellulose (4.5 parts) and lactose (5.5 parts).

The “core” may contain the physiologically active substance such as theabove described pharmaceutical ingredient. Also, the “core” may notcontain the physiologically active substance because the release of thephysiologically active substance can be controlled by a coating layercontaining the physiologically active substance.

The “core” is preferably as uniform a sphere as possible, for reducingthe irregularity of the coating, in addition to being a powdery core.

The ratio of the “coating layer” to the “core” can be selected withinthe range in which it is possible to control dissolution of thephysiologically active substance and particle size of the composition,for example, usually about 50 to 400 weight % relative to 100 weight %of the core.

The coating layer may be constructed by plural layers. At least onelayer of the plural layers must contain the physiologically activesubstance. The combination of various layers such as a coating layer notcontaining the active ingredient, a base coating layer, and an entericcoating layer which constitute the coating layer can be suitablyselected.

Incase that the “core” is coated, for example, the above physiologicallyactive substance and the water-soluble polymer can be employed inadmixture thereof. The admixture may be a solution or a dispersion, andcan be prepared by using an organic solvent such as water or ethanol oran admixture thereof.

The concentration of the water-soluble polymer in the admixture variesaccording to the ratio of the physiologically active substance and theexcipients, and is usually about 0.1 to 50 weight %, preferably about0.5 to 10 weight %, in order to retain the binding strength of thephysiologically active substance to the core and maintain the viscosityof the mixture so as not to reduce the workability.

Where the coating layer comprises plural layers, the concentration ofthe physiologically active substance in each layer may be changedsuccessively or gradually by selecting for the content ratio orviscosity of the water-soluble polymer or by successive coating withmixtures varying in the ratio of the physiologically active substanceand the other excipients. In the above case, it may be coated with amixture in which the content ratio of the water-soluble polymer is outof the range of about 0.1 to 50 weight %, as long as the coating layeras a whole contains about 0.1 to 50 weight of the water-soluble polymer.Further, in forming the inactive coat according to known methods, thecoating layer may comprise some layers such that the inactive layer mayblock each layer containing the physiologically active substance.

Also, in case of two or more physiologically active substances notsuited in the compatibility, the core may be coated by employing eachmixture together or separately.

The above coated material is dried, and passed through sieves to obtaina “composition” having uniform size. Because the form of the powder isusually according to the core, a fine granule being in the form of arough sphere may be obtained. As the sieve may be employed, for examplea #50 circular sieve (300 μm). The composition is obtained by selectingthose which pass through the #50 circular sieve.

The “fine granule” in the present invention can be produced inaccordance with in the same manner as above granulation method, forexample, a method which comprises coating the composition with anenteric coating layer, in order to protect the acid-labilephysiologically active substance or to impart enteric dissolution. Ifnecessary, the composition coated with an enteric coating layer may befurther coated by a water-soluble sugar alcohol, preferably mannitol.

In such case, the strength of the orally disintegrable tablet comprisingfine granules is improved.

The “enteric coating layer” is preferably a layer having about 20 to 70μm, preferably about 30 to 50 μm of thickness and coating the wholesurface of the composition containing the physiologically activesubstance. Accordingly, the smaller particle diameter of thecomposition, the higher the weight % of the enteric coating layer in thewhole fine granule. In the fine granule of the present invention, the“enteric coating layer” is about 30 to 70 weight %, preferably about 50to 70 weight %, of the fine granule as a whole.

The “enteric coating layer” may be constructed by plural (e.g., 2 or 3)layers. For example, employed is a method which comprises coating acomposition with an enteric coating layer having polyethyleneglycol, andthen with an enteric coating layer having triethyl citrate, followed bybeing coated with an enteric coating layer having polyethyleneglycol.

The “orally disintegrable tablet” of the present invention can beproduced in accordance with a conventional method in the pharmaceuticalfield. Such methods include, for instance, a method which comprisesblending the “fine granules” and the “additives”, and molding, ifnecessary followed by drying. Concretely mentioned is a method whichcomprises blending the fine granules and the additives, if necessarywith water, and molding, if necessary followed by drying.

The “blending procedure” can be carried out by any of the conventionalblending techniques such as admixing, kneading, granulating, etc. Theabove “blending procedure” is carried out, for instance, by using anapparatus such as Vertical

Granulator GV10 [manufactured by Powrex Corp. (Japan)], UniversalKneader [manufactured by Hata Iron Works Co., Ltd. (Japan)], fluidizedbed granulator LAB-1 and FD-3S [manufactured by Powrex Corp. (Japan)],V-shape mixer, tumbling mixer, and so forth.

Preferred example of the method for the “orally disintegrable tablet” ofthe present invention is a method which comprises:

(i) coating a core comprising crystalline cellulose and lactose with anacid-labile physiologically active substance and a basic inorganic salt,followed by being coated with a coating layer comprising a water-solublepolymer to obtain a composition,(ii) coating the resultant composition with an enteric coating layerhaving polyethyleneglycol, and then with an enteric coating layer havingtriethyl citrate, and then with an enteric coating layer havingpolyethyleneglycol, followed by being coated by mannitol to obtain finegranule, and(iii) blending the resultant fine granule with an additive, followed bymolding.

Where the pharmaceutical preparation of the present invention,especially an orally disintegrable tablet, is one which comprises nolubricant inside the preparation or tablet, such preparation can bepreferably produced in accordance with methods described inJP-A-56-14098, Japanese Patent No. 2681601, etc. Such preparation,especially an orally disintegrable tablet, has sufficient strength. Theabove lubricant includes, for example, magnesium stearate, sucrose fattyacid ester, polyethyleneglycol, talc, stearic acid, etc.

The pharmaceutical preparations such as solid preparation (e.g.,tablets, granules, fine granules, capsules, effervescents, etc.) andliquid preparation such as suspending preparation, which comprises the“fine granules” of the present invention can be produced in accordancewith a conventional method.

The solid pharmaceutical preparation containing the “fine granules” ofthe present invention and the “orally disintegrable tablet” of theinvention can also be produced by the wet tabletting method. As theabove method, it is preferably employed the methods described inJP-A-5-271054 and so forth. The_(y) can also be produced by drying afterhumidification. As the above method, preferably employed are the methodsdescribed in JP-A-9-48726, JP-A-8-291051 and so forth. Namely, it iseffective to humidify before tabletting or after tabletting and then todry, in order to enhance the hardness.

The “molding procedure” can be carried out, for instance, by tablettingwith a pressure of 0.5 to 3 ton/cm², preferably 1 to 2 ton/cm² by usinga single-punch tabletting machine [Kikusui Seisakusho (Japan)] or arotary type tabletting machine [Kikusui Seisakusho (Japan)] when a solidpreparation is a tablet, especially an orally disintegrable tablet.

The “drying procedure” can be carried out by any of the techniques usedcommonly in the art, such as vacuum drying, fluidized-bed drying, etc.

The “fine granules” of the invention can be used for a pharmaceuticalpreparation. The pharmaceutical preparation includes, for example, asolid preparation such as tablet, granule, fine granule, capsule,effervescent, etc.; a liquid preparation such as a suspensionpreparation, etc. Among others, a tablet is preferred. Such tabletpreferably has suitable strength so as to be stable through productionprocesses and distributions.

A solid pharmaceutical preparation comprising the fine granule of theinvention is used for an orally disintegrable tablet and can beadministered without water or together with water.

As administration methods, there are listed (1) a method ofadministration by dissolution or disintegration together with a littlewater, or without water and with saliva in the oral cavity, not to beswallowed as it is, or (2) a method of administration with water, whereit is swallowed as it is.

Also, the tablet may be administered dissolved or disintegrated withwater.

The “orally disintegrable tablet” of the present invention isadvantageously used in (a) cases where administration without water isnecessary, (b) cases of administration to a patients who have difficultyin swallowing tablets, or (c) cases of administration to the aged or tochildren where there is a fear of blocking the throat if it is in usualtablet form.

In case of the above (a), the orally disintegrable tablet is preferablyused for antipyretic agents, analgesic agents, anti-inflammatory agents,antianxiety drugs, antitussive-expectorants, anti motion sicknessagents, drugs for prevention and treatment for car-sickness, and soforth.

In case of the above (b), the orally disintegrable tablet is preferablyused for preventing and/or treating hypertension, hyperlipemia,diabetes, bronchial asthma, cerebrovascular diseases, and so forth.

The “orally disintegrable tablet” of the present invention and thepharmaceutical preparation which comprises the “fine granules” of thepresent invention can be safely administered orally to mammals such asmice, rats, rabbits, cats, dogs, bovines, horses, monkeys, humans, etc.

With the dosage of the “orally disintegrable tablet” of the presentinvention and the pharmaceutical preparation which comprises the “finegranules” of the present invention, varies depending on thepharmaceutically active ingredient, subject, kinds of diseases, etc.,the dosage can be selected so that the dosage of the pharmaceuticallyactive ingredient is an effective amount.

For instance, when a benzimidazole compound (I) or a salt thereof suchas lansoprazole is employed as an acid-labile physiologically activesubstance, especially a pharmaceutically active ingredient, the “orallydisintegrable tablet” of the present invention and the pharmaceuticalpreparation which comprises the “fine granules” of the present inventionis useful for treatment and prevention of digestive ulcer (e.g., gastriculcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome,etc), gastritis, reflux esophagitis, etc.; eradication of H. pylori;suppression of gastrointestinal bleeding caused by digestive ulcer,acute stress ulcer and hemorrhagic gastritis; suppression ofgastrointestinal bleeding caused by invasive stress (e.g., stress causedby cerebrovascular disease, head injury, failure of many organs, burninjury of a wide range, which necessitate a large-scale operationnecessitating the following intensive management, or intensive care);treatment and prevention of ulcer caused by non-steroidalanti-inflammatory agent; treatment and prevention of gastrichyperacidity and ulcer caused by postoperative stress; administrationbefore anesthesia, etc. The dosage of the preparation per an adult (bodyweight:60 kg) is about 0.5 to 1,500 mg/day, preferably about 5 to 150mg/day, as a benzimidazole compound (I) or a salt thereof such aslansoprazole.

The “orally disintegrable tablet” of the present invention and thepharmaceutical preparation which comprises the “fine granules” of thepresent invention can be administered once a day, or two or three timesseparately a day.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Examples and Reference Examples are further illustrativebut by no means limitative of the present invention.

Unless otherwise specifically indicated, the following “%” means weight%.

Also, the content of the hydroxypropoxyl group is measured in accordancewith the methods described in Japanese Pharmacopoeia (13th edition).

The physical properties of the tablets and granules prepared in Exampleswere determined by the following test methods.

(1) Hardness Test

Determination was carried out with a tablet hardness tester[manufactured by Toyama Sangyo, Co. Ltd. (Japan)]. The test wasperformed in 10 runs and mean values were shown.

(2) Oral Disintegration Time

Time for complete disintegration only by saliva in the oral cavity wasdetermined.

(3) Remaining Ratio

According to the 2nd method of the dissolution test defined in JapanesePharmacopoeia, the dissolution test was performed by using 500 ml of0.1N HCl (75 rpm) for 1 hour. Then, the enteric fine granule wascollected by means of the sieve.

The content of the drug in the collected fine granule was measured bythe HPLC method. The remaining ratio was calculated according to thefollowing expression with the content of the drug in the tablet which ismeasured separately by HPLC method.

Remaining ratio=(Content of the drug in the collected fine granule afterthe dissolution test using 0.1N HCl for 1 hour)/(Content of the drug inthe tablet)

(4) Acid-Resistance: Dissolution Using 0.1N HCl

According to the 2nd method of the dissolution test defined in JapanesePharmacopoeia, the dissolution test was performed by using 500 ml of0.1N HCl (75 rpm) for 1 hour. Then, test medium was collected andfiltered by using a 0.45 μm membrane filter. The absorbance was measuredto calculate the dissolution of the drug into 0.1N HCl.

(5) Average Particle Diameter: Volume Based Distribution Median Diameter(Median Diameter: 50% Particle Diameter from Cumulative Distribution)

Determination was carried out with Raser Diffraction Analyzer, type:HEROS RODOS [trade name, manufactured by Sympatec (Germany)].

EXAMPLES Example 1 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] is charged with 300 g of Nonpareil 105 (70-140)(particle diameter of 100 to 200 μm). With the inlet air temperature andthe temperature of the loading being controlled at 85° C. and about 28°C. respectively, the Nonpareil is coated by spraying a bulk liquid ofthe following composition prepared in advance in accordance with thetangential spray method at a spray rate of 20 g/min. The sprayingoperation is stopped when the specified amount of the bulk liquid hasbeen sprayed, and then drying is carried out in the granulator for 7minutes. The resulting granules are sieved through a #60 circular sieve(250 μm) and a #100 circular sieve (150 μm) to provide 750 g of granuleshaving a core.

Bulk Liquid:

Lansoprazole 300 g Magnesium carbonate 100 g L-HPC  50 g HPC (Type SSL)100 g Water 1650 g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] is charged with 680 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 70° C. and about 36° C., respectively, anundercoating liquid of the following composition prepared in advance issprayed in accordance with the tangential spray method at a spray rateof 10 g/min. to provide 650 g of film-undercoated granules having acore.

Undercoating Liquid:

HPMC 32 g (Type 2910, viscosity: 3 centistokes) Talc  8 g Water 760 g 

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] is charged with 450 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 65° C. and about36° C., respectively, an enteric film coating liquid of the followingcomposition prepared in advance is sprayed in accordance with thetangential spray method at a spray rate of 17 g/min. The coated powdersare dried in vacuum at 40° C. for 16 hours, and sieved through a #42circular sieve (355 μm) and a #80 circular sieve (177 μm) to provide 950g of enteric coated granules having a core.

Enteric Film Coating Liquid:

Eudragit L30D-55 1078.3 g  Eudragit NE30D 138.5 g  Triethyl citrate 46.0g Glyceryl monostearate 23.1 g Talc 16.0 g Polysorbate 80  9.0 g Yellowiron oxide  0.5 g Water 2038.5 g  Sieve weight ratio  #18 (850 μm) on 0% #30 (500 μm) on 0% #200 (75 μm) on 100%  #200 (75 μm) pass 0%

(4) Production of Granulated Powders

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]is charged with 1321.2 g of erythritol [manufactured by Nikken ChemicalCo., Ltd. (Japan)], 360.0 g of low-substituted hydroxypropyl celluloseLH-32 [hydroxypropoxyl group contents of 8.8%, manufactured by Shin-EtsuChemical Co., Ltd. (Japan)], 18.0 g of citric acid anhydrous, and 1.8 gof aspartame, and granulation is carried out while spraying a solutionwhich is prepared by dissolving 3.6 g of polyethylene glycol (PEG-6000)in 896.4 ml of purified water. The granules are dried to providegranulated powders. To the granulated powders are added 90.0 g ofcrospovidone and 5.4 g of magnesium stearate, which is admixed in a bagto give mixed powders.

(5) Production of Orally Disintegrable Tablets

Hereinafter, the above “enteric coated granules having a core” isreferred to as “enteric coated powders”.

200.0 g of the above enteric coated powders and 300.0 g of the abovemixed powders are tabletted using Autograph (trade name; compressingforce measurement apparatus) with a punch having a beveled edge, 11 mmin diameter, at a tabletting pressure of 1.0 ton/cm² to provide tabletseach weighing 500 mg.

Reference Example 1

An alkaline cellulose comprising 24.1% of NaOH, 1.7% of Na₂CO₃, 42.9% ofcellulose, 31.8% of H₂O was obtained by immersing a wood pulp in 49%aqueous solution of sodium hydroxide and then by pressing it. A reactorwas charged with 100 weight parts of the alkaline cellulose. Then,nitrogen gas replacement was carried out. After the replacement, 5weight parts of propylene oxide was charged in the reactor and reactedwith stirring at 40° C. for 1 hour, at 50° C. for 1 hour and at 70° C.for 1 hour to obtain 103 weight parts of a reactant.

On the other side, a kneader was charged with 2.5 weight parts of hotwater at 65° C. and 0.13 weight parts of glacial acetic acid (about 40weight % against equivalent for neutralization, initial neutralizedacid) and therein, 1 weight part of the above resulting alkalinecellulose was dispersed. Then, the temperature was set at 30° C. todissolve a part of the reactant, and 0.20 weight part of glacial aceticacid (the remainder of an equivalent for neutralization, completeneutralized acid) to obtain a processed fiber product containing a partof dissolution and a part of deposit.

The resulting product was washed with hot water at about 80° C.,drained, dried, ground by means of a high rolling impact grinder, andsifted by means of a 100 mesh sieve to obtain the powder oflow-substituted hydroxypropyl cellulose LH-33 (the content ofhydroxypropoxyl group: 5.8 weight %, the average particle diameter: 17.8μm).

Reference Example 2

Powders of low-substituted hydroxypropyl cellulose LH-23(hydroxypropoxyl group contents: 5.7 weight %, average particlediameter: 30.8 μm) were obtained in the same manner as in ReferenceExample 1.

Example 2 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 300 g of Nonpareil 105 [(tradename) particle diameter: 100 to 200 μm]. With the inlet air temperatureand the temperature of the loading being controlled at 70° C. and about30° C., respectively, the Nonpareil was coated by spraying a sprayliquid of the following composition prepared in advance in accordancewith the tangential spray method at a spray rate of 22 g/min., and thendrying was carried out in the granulator for 10 minutes. The resultinggranules were sieved through a #48 circular sieve (300 μm) and a #100circular sieve (150 μm) to provide 2186 g of powders (150 to 300 μm)having a core.

Spray Liquid:

Lansoprazole 927 g Magnesium carbonate 309 g Low-substitutedhydroxypropyl cellulose LH-32 154.5 g   (hydroxypropoxyl group contents:8.8 wt %) (average particle diameter: 17.57 μm) Hydroxypropyl cellulose(Type SSL) 309 g Purified water 3955 g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 2040 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 75° C. and about 40° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 13 g/min. to provide 2145 g of film-undercoated granules having acore.

Undercoating Liquid:

Hydroxypropylmethylcellulose 264 g (Type 2910, viscosity: 3 centistokes)Purified water 5016 g 

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1710 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 70° C. and about40° C., respectively, an enteric film coating liquid of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 17 g/min., and dried for 7minutes, and then sieved through a #42 circular sieve (355 μm) and a #80circular sieve (177 μm) to provide 2393 g of enteric coated powders (177to 355 μm) having a core.

Enteric Film Coating Liquid:

Eudragit L30D-55 5016.4 g  Eudragit NE30D 559.0 g Triethyl citrate 333.7g Glyceryl monostearate 106.5 g Polysorbate 80  34.8 g Red iron oxide 1.8 g Purified water 2547.1 g 

(4) Production of Enteric Coated and Mannitol Coated Granules Having aCore

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 600 g of the above entericcoated granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 65° C. and about 32° C.,respectively, an film coating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 11 g/min., and then dried for 7 minutes toprovide 617 g of enteric coated and mannitol coated granules having acore.

The average particle diameter of the obtained granules was 334.1 μm.

Film Coating Liquid:

Mannitol 33 g Purified water 297 g 

(5) Production of Mannitol-Granulated Powders

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 800 g of mannitol [manufactured by Merck Japan Co.,Ltd.], and granulation was carried out while spraying 315 g of purifiedwater. The granules were dried to provide 727.3 g of granulated powders.

(6) Production of Mixed Powders

To 97.3 g of the above mannitol-granulated powders were added 105 g ofthe above enteric coated and mannitol coated granules having a core,15.0 g of low-substituted hydroxypropyl cellulose LH-33 (hydroxypropoxylgroup contents: 5.8 weight %, average particle diameter: 17.8 μm), 22.5g of crystalline cellulose [CEOLUS KG-801 (trade name), manufactured byAsahi Chemical Co., Ltd. (Japan)], 7.5 g of crospovidone, 1.5 g ofcitric acid anhydrous, 0.45 g of aspartame and 0.75 g of magnesiumstearate, which was admixed in a bag to give mixed powders.

(7) Production of Orally Disintegrable Tablets

250.0 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch (15R), 11 mmin diameter, at a tabletting pressure of 1.5 ton/cm², to provide tabletseach weighing 500 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 5.9 kg and 30 seconds, respectively.

Example 3 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 900 g of Nonpareil 105 (tradename) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 75°C. and about 29° C. respectively, the Nonpareil was coated by spraying abulk liquid of the following composition prepared in advance inaccordance with the tangential spray method at a spray rate of 22 g/min.The spraying operation was stopped when the specified amount 5654.7 g ofthe bulk liquid had been sprayed, and then drying was carried out in thegranulator for 10 minutes. The resulting granules were sieved through a#60 circular sieve (250 μm) and a #100 circular sieve (150 μm) toprovide 2424 g of granules having a core.

Bulk Liquid:

Lansoprazole 1080 g  Magnesium carbonate 360 g Low-substitutedhydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8weight %) Hydroxypropyl cellulose (Type SSL) 360 g Purified water 4608g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured byPowrexCorp.(Japan), MP-10 (Type 2)] was charged with 2337.5 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 80° C. and about 41° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 18 g/min. The spraying operation was stopped when the specifiedamount 6050 g of the undercoating liquid had been sprayed, and thendrying was carried out in the granulator for 10 minutes to provide 2551g of film-undercoated granules having a core.

Undercoating Liquid:

Hydroxypropyl methylcellulose 332.5 g (Type 2910, viscosity: 3centistokes) Low-substituted hydroxypropyl cellulose LH-32  17.5 g(hydroxypropoxyl group contents: 8.8 weight %) (average particlediameter: 17.57 μm) Purified water  6650 g

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 570 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 75° C. and about40° C., respectively, an enteric film coating liquid of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 18 g/min. The sprayingoperation was stopped when the specified amount 2646 g of the entericfilm coating liquid had been sprayed, and then drying was carried out inthe granulator for 8 minutes. The coated powders were sieved through a#42 circular sieve (355 μm) and a #70 circular sieve (212 μm) to provide1116 g of enteric coated granules having a core.

The average particle diameter of the obtained granules was 326.9 μm.

Enteric Film Coating Liquid:

Eudragit L30D-55  1911 g Eudragit NE30D 212.9 g Triethyl citrate 127.1 gGlyceryl monostearate  40.6 g Polysorbate 80  13.3 g Red iron oxide  0.8g Purified water 970.3 g

(4) Production of Mixed Powders

To 200 g of the above enteric coated granules having a core were added189.7 g of mannitol, 30.0 g of low-substituted hydroxypropyl celluloseLH-23 (hydroxypropoxyl group contents: 5.8 weight %, average particlediameter: 17.8 μm), 60.0 g of crystalline cellulose [CEOLUS KG-801(trade name), manufactured by Asahi Chemical Co., Ltd. (Japan)], 15.0 gof crospovidone, 2.8 g of citric acid anhydrous and 25 g of magnesiumstearate, which was admixed in a bag to give mixed powders.

(5) Production of Orally Disintegrable Tablets

250.0 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch (15R), 11 mmin diameter, at a tabletting pressure of 1.5 ton/cm², to provide tabletseach weighing 500 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 4.2 kg and 24 seconds, respectively.

Example 4 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 900 g of Nonpareil 105 (tradename) (particle diameter of 100 to 200 μm).

With the inlet air temperature and the temperature of the loading beingcontrolled at 75° C. and about 32° C. respectively, the Nonpareil wascoated by spraying a bulk liquid of the following composition preparedin advance in accordance with the tangential spray method at a sprayrate of 20 g/min. The spraying operation was stopped when the specifiedamount 5654.7 g of the bulk liquid had been sprayed, and then drying wascarried out in the granulator for 10 minutes. The resulting granuleswere sieved through a #48 circular sieve (300 μm) and a #100 circularsieve (150 μm) to provide 2280 g of granules having a core.

Bulk Liquid:

Lansoprazole 1080 g  Magnesium carbonate 360 g Low-substitutedhydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8weight %) Hydroxypropyl cellulose (Type SSL) 360 g Purified water 4608g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1020 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 85° C. and about 40° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 15 g/min. The spraying operation was stopped when the specifiedamount 1980 g of the undercoating liquid had been sprayed, and thendrying was carried out in the granulator for 10 minutes to provide1330.5 g of film-undercoated granules having a core.

Undercoating Liquid:

Hydroxypropylmethylcellulose 120 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 240 g Sterilized Talc (trade name) 240 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Magnesium carbonate 120 g Purifiedwater 2880 g 

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 460 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 80° C. and about41° C., respectively, an enteric film coating liquid of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 13 g/min. The sprayingoperation was stopped when the specified amount 2205 g of the entericfilm coating liquid had been sprayed.

Enteric Film Coating Liquid:

Eudragit L30D-55 2290 g  Eudragit NE30D 253 g  Triethyl citrate 153 g Glyceryl monostearate 20 g Polysorbate 80  8 g Titanium oxide (TiO₂) 53g Sterilized Talc H (trade name) 53 g [produced by Matsumura Sangyo Co.Ltd. (Japan)] Purified water 2420 g 

(4) Production of Enteric Coated and Mannitol Coated Granules Having aCore

Following (3), with the inlet air temperature and the temperature of theloading being controlled at 80° C. and about 35° C., respectively, anfilm coating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 16 g/min. using a centrifugal fluidized coating granulator[manufactured by Powrex Corp. (Japan), MP-10 (Type 2)]. The sprayingoperation was stopped when the specified amount 824 g of the filmcoating liquid had been sprayed, and then drying was carried out in thegranulator for 10 minutes. The resulting granules were sieved through a#42 circular sieve (355 pin) and a #60 circular sieve (250 μm) toprovide 806 g of enteric coated and mannitol coated granules having acore.

The average particle diameter of the obtained granules was 326.6 μm.

Film Coating Liquid:

Mannitol  320 g Purified water 2880 g

(5) Production of Mixed Powders

To 120 g of the above enteric coated and mannitol coated granules havinga core were added 87.75 g of mannitol, 8.5 g of low-substitutedhydroxypropyl cellulose LH-23 (hydroxypropoxyl group contents: 5.8weight %), 4.5 g of low-substituted hydroxypropyl cellulose LH-33(hydroxypropoxyl group contents: 5.8 weight %), 19.5 g of crystallinecellulose [CEOLUS KG-801 (trade name), manufactured by Asahi ChemicalCo., Ltd. (Japan)], 6.5 g of crospovidone, 1.3 g of citric acidanhydrous, 1.3 g of aspartame and 0.65 g of magnesium stearate, whichwas admixed in a bag to give mixed powders.

(6) Production of Orally Disintegrable Tablets

250.0 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch (15R), 11 mmin diameter, at a tabletting pressure of 1.5 ton/cm², to provide tabletseach weighing 500 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 3.9 kg and 20.5 seconds, respectively.

The remaining ratio of the obtained tablet after acid-resistance testwas 97%.

Example 5 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 900 g of Nonpareil 105 (tradename) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 65°C. and about 30° C. respectively, the Nonpareil was coated by spraying abulk liquid of the following composition prepared in advance inaccordance with the tangential spray method at a spray rate of 22 g/min.The spraying operation was stopped when the specified amount 5661 g ofthe bulk liquid had been sprayed, and then drying was carried out in thegranulator for 8 minutes.

The resulting granules were sieved through a #42 circular sieve (350 μm)and a #100 circular sieve (150 μm) to provide 2074 g of granules havinga core.

Bulk Liquid:

Lansoprazole 1080 g  Magnesium carbonate 360 g Low-substitutedhydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8weight %) Hydroxypropyl cellulose (Type SSL) 360 g Purified water 4680g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 2074 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 78° C. and about 40° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 22 g/min. The spraying operation was stopped when the specifiedamount 1980 g of the undercoating liquid had been sprayed, and thendrying was carried out in the granulator for 9 minutes. The resultinggranules were sieved through a #42 circular sieve (350 μm) and a #100circular sieve (150 μm) to provide 2555 g of film-undercoated granuleshaving a core.

Undercoating Liquid:

Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 108 g Sterilized Talc (trade name) 108 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Low-substituted hydroxypropylcellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight %)Mannitol 252 g Purified water 3600 g 

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator (manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1320 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 80° C. and about42° C., respectively, an enteric film coating liquid (A) of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 22 g/min. The specifiedamount 1638 g of the enteric film coating liquid had been sprayed.

Enteric Film Coating Liquid (A):

Eudragit L30D-55 1219.2 g   Eudragit NE30D 134.4 g  Polyethylene glycol6000 40.8 g Glyceryl monostearate 24.0 g Polysorbate 80  7.2 g Ferricoxide 0.24 g Ferric oxide (yellow) 0.24 g Citric acid anhydrous 0.48 gPurified water 1693 g 

Following this, with the inlet air temperature and the temperature ofthe loading being controlled at 76° C. and about 42° C., respectively,an enteric film coating liquid (B) of the following composition preparedin advance was sprayed in accordance with the tangential spray method ata spray rate of 22 g/min. The specified amount 6552 g of the entericfilm coating liquid had been sprayed.

Enteric Film Coating Liquid (B):

Eudragit L30D-55 4032 g  Eudragit NE30D 447.8 g  Triethyl citrate 269.3g  Glyceryl monostearate 86.4 g Polysorbate 80 25.9 g Ferric oxide 0.86g Ferric oxide (yellow) 0.86 g Citric acid anhydrous 0.72 g Purifiedwater 2624 g 

Following this, with the inlet air temperature and the temperature ofthe loading being controlled at 80° C. and about 42° C., respectively,an enteric film coating liquid (A) of the above mentioned compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 22 g/min. The specified amount 819 g of theenteric film coating liquid had been sprayed.

(4) Production of Enteric Coated and Mannitol Coated Granules Having aCore

Following (3), with the inlet air temperature and the temperature of theloading being controlled at 85° C. and about 35° C., respectively, anfilm coating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 22 g/min. using a centrifugal fluidized coating granulator[manufactured by Powrex Corp. (Japan), MP-10 (Type 2)]. The sprayingoperation was stopped when the specified amount 882 g of the filmcoating liquid had been sprayed, and then drying was carried out in thegranulator for 10 minutes. The resulting granules were sieved through a#35 circular sieve (420 μm) and a #60 circular sieve (250 μm) to provide1964 g of enteric coated and mannitol coated granules having a core.

The average particle diameter of the obtained granules was 333.7 μm.

Film Coating Liquid:

Mannitol  180 g Purified water 1080 g

(5) Production of Mixed Powders

To 270 g of the above enteric coated and mannitol coated granules havinga core were added 204.0 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

(6) Production of Orally Disintegrable Tablets

570 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch having abeveled edge, 13 mm in diameter, at a tabletting pressure of 1.5ton/cm², to provide tablets each weighing 570 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 2.6 kg and 20 seconds, respectively.

The acid-resistance of the obtained tablet was 3.5%.

Example 6 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 750 g of Nonpareil 105 (tradename) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 65°C. and about 30° C. respectively, the Nonpareil was coated by spraying abulk liquid of the following composition prepared in advance inaccordance with the tangential spray method at a spray rate of 22 g/min.The spraying operation was stopped when the specified amount 4717.5 g ofthe bulk liquid had been sprayed, and then drying was carried out in thegranulator for 8 minutes. The resulting granules were sieved through a#42 circular sieve (350 μm) and a #100 circular sieve (150 μm) toprovide 1811 g of granules having a core.

Bulk Liquid:

Lansoprazole 900 g Magnesium carbonate 300 g Low-substitutedhydroxypropyl cellulose LH-32 150 g (hydroxypropoxyl group contents: 8.8weight %) Hydroxypropyl cellulose (Type SSL) 300 g Purified water 3900g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1811 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 78° C. and about 38° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 22 g/min. The spraying operation was stopped when the specifiedamount 5274 g of the undercoating liquid had been sprayed, and thendrying was carried out in the granulator for 9 minutes. The resultinggranules were sieved through a #42 circular sieve (350 μm) and a #100circular sieve (150 μm) to provide 2628 g of film-undercoated granuleshaving a core.

Undercoating Liquid:

Hydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 162 g Sterilized Talc (trade name) 162 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Low-substituted hydroxypropylcellulose LH-32 270 g (hydroxypropoxyl group contents: 8.8 weight %)Mannitol 378 g Purified water 5400 g 

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1560 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 70° C. and about40° C., respectively, an enteric film coating liquid (A) of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 19 g/min. The specifiedamount 6048 g of the enteric film coating liquid had been sprayed.

Enteric Film Coating Liquid (A):

Eudragit L30D-55 4032 g  Eudragit NE30D 447.8 g  Triethyl citrate 269.3g  Glyceryl monostearate 86.4 g Polysorbate 80 25.9 g Ferric oxide 0.86g Ferric oxide (yellow) 0.86 g Citric acid anhydrous 0.72 g Purifiedwater 2624 g 

Following this, with the inlet air temperature and the temperature ofthe loading being controlled at 72° C. and about 42° C., respectively,an enteric film coating liquid (B) of the following composition preparedin advance was sprayed in accordance with the tangential spray method ata spray rate of 19 g/min. The specified amount 819 g of the enteric filmcoating liquid had been sprayed.

Enteric Film Coating Liquid (B):

Eudragit L30D-55 609.6 g Eudragit NE30D 68.0 g Polyethylene glycol 600020.4 g Glyceryl monostearate 12.0 g Polysorbate 80 3.6 g Ferric oxide0.12 g Ferric oxide (yellow) 0.12 g Citric acid anhydrous 0.24 gPurified water 846.7 g

(4) Production of Enteric Coated and Mannitol Coated Granules Having aCore

Following (3), while the inlet air temperature and the temperature ofthe loading being controlled at 65° C. and about 38° C., respectively,an film coating liquid of the following composition prepared in advancewas sprayed in accordance with the tangential spray method at a sprayrate of 19 g/min. using a centrifugal fluidized coating granulator[manufactured by Powrex Corp. (Japan), MP-10 (Type 2)]. The sprayingoperation was stopped when the specified amount 882 g of the filmcoating liquid had been sprayed, and then drying was carried out in thegranulator for 17 minutes. The resulting granules were sieved through a#35 circular sieve (420 μm) and a #60 circular sieve (250 μm) to provide2825 g of enteric coated and mannitol coated granules having a core.

The average particle diameter of the obtained granules was 330.5 μm.

Film Coating Liquid:

Mannitol  180 g Purified water 1080 g

(5) Production of Mixed Powders

To 270 g of the above enteric coated and mannitol coated granules havinga core were added 204.0 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

(6) Production of Orally Disintegrable Tablets

570 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch having abeveled edge, 13 mm in diameter, at a tabletting pressure of 1.5ton/cm², to provide tablets each weighing 570 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 3.1 kg and 22 seconds, respectively.

The acid-resistance of the obtained tablet was 2.5%.

Example 7 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 750 g of Nonpareil 105 (tradename) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 75°C. and about 30° C. respectively, the Nonpareil was coated by spraying abulk liquid of the following composition prepared in advance inaccordance with the tangential spray method at a spray rate of 20 g/min.The spraying operation was stopped when the specified amount 4717.5 g ofthe bulk liquid had been sprayed, and then drying was carried out in thegranulator for 10 minutes to provide 1842 g of granules having a core.

Bulk Liquid:

Lansoprazole 900 g Magnesium carbonate 300 g Low-substitutedhydroxypropyl cellulose LH-32 150 g (hydroxypropoxyl group contents: 8.8weight %) Hydroxypropyl cellulose (Type SSL) 300 g Purified water 3900g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2) was charged with 1842 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 74° C. and about 38° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 19 g/min. The spraying operation was stopped when the specifiedamount 5365 g of the undercoating liquid had been sprayed, and thendrying was carried out in the granulator for 9 minutes. The resultinggranules were sieved through a #42 circular sieve (350 μm) and a #100circular sieve (150 μm) to provide 2770 g of film-undercoated granuleshaving a core.

Undercoating Liquid:

Hydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 162 g Sterilized Talc (trade name) 162 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Low-substituted hydroxypropylcellulose LH-32 270 g (hydroxypropoxyl group contents: 8.8 weight %)Mannitol 378 g Purified water 5400 g 

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1300 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 78° C. and about39° C., respectively, an enteric film coating liquid (A) of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 21 g/min. The sprayingoperation was stopped when the specified amount 5040 g of the entericfilm coating liquid had been sprayed, and then drying was carried out inthe granulator for 16 minutes. The resulting granules were sievedthrough a #35 circular sieve (420 μm) and a #60 circular sieve (250 μm)to provide 2453 g of enteric coated granules having a core.

Enteric Film Coating Liquid (A):

Eudragit L30D-55 4032 g Eudragit NE30D 447.8 g Triethyl citrate 269.3 gGlyceryl monostearate 86.4 g Polysorbate 80 25.9 g Ferric oxide 0.86 gFerric oxide (yellow) 0.86 g Citric acid anhydrous 0.72 g Purified water2624 g

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1000 g of the above entericcoated granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 80° C. and about 38° C.,respectively, an enteric film coating liquid (B) of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 19 g/min. The specifiedamount 273 g of the enteric film coating liquid had been sprayed.

Enteric Film Coating Liquid (B):

Eudragit L30D-55 610.4 g Eudragit NE30D 68.0 g Polyethylene glycol 600020.4 g Glyceryl monostearate 12.0 g Polysorbate 80 3.6 g Ferric oxide0.12 g Ferric oxide (yellow) 0.12 g Citric acid anhydrous 0.24 gPurified water 845.12 g

(4) Production of Enteric Coated and Mannitol Coated Granules Having aCore

Following (3), while the inlet air temperature and the temperature ofthe loading being controlled at 75° C. and about 35° C., respectively,an film coating liquid of the following composition prepared in advancewas sprayed in accordance with the tangential spray method at a sprayrate of 20 g/min. using a centrifugal fluidized coating granulator[manufactured by Powrex Corp. (Japan), MP-10 (Type 2)]; The sprayingoperation was stopped when the specified amount 294 g of the filmcoating liquid had been sprayed, and then drying was carried out in thegranulator for 10 minutes. The resulting granules were sieved through a#35 circular sieve (420 μm) and a #60 circular sieve (250 μm) to provide1061 g of enteric coated and mannitol coated granules having a core.

The average particle diameter of the obtained granules was 307.1 μm.

Film Coating Liquid:

Mannitol 120 g Purified water 720 g

(5) Production of Mixed Powders

To 270 g of the above enteric coated and mannitol coated granules havinga core were added 207 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

(6) Production of Orally Disintegrable Tablets

570 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch having abeveled edge, 13 mm in diameter, at a tabletting pressure of 1.5ton/cm², to provide tablets each weighing 570 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 3.2 kg and 24 seconds, respectively.

Example 8 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 900 g of Nonpareil 105T (tradename) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 71 to78° C. and about 31° C. respectively, the Nonpareil was coated byspraying a bulk liquid of the following composition prepared in advancein accordance with the tangential spray method at a spray rate of 21g/min. The spraying operation was stopped when the specified amount 5550g of the bulk liquid had been sprayed, and then drying was carried outin the granulator for 21 minutes. The resulting granules were sievedthrough a #42 circular sieve (350 μm) and a #100 circular sieve (150 μm)to provide 1723 g of granules having a core.

Bulk Liquid:

Lansoprazole 1080 g  Magnesium carbonate 360 g Low-substitutedhydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8weight %) Hydroxypropyl cellulose (Type SSL) 360 g Purified water 4680g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 2074 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 77° C. and about 41° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 21 g/min. The spraying operation was stopped when the specifiedamount 2787 g of the undercoating liquid had been sprayed, and thendrying was carried out in the granulator for 13 minutes. The resultinggranules were sieved through a #42 circular sieve (350 μm) and a #100circular sieve (150 μm) to provide 1958 g of film-undercoated granuleshaving a core.

Undercoating Liquid:

Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 108 g Sterilized Talc (trade name) 108 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Low-substituted hydroxypropylcellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight %)Mannitol 252 g Purified water 3600 g 

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 1100 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 80° C. and about41° C., respectively, an enteric film coating liquid (A) of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 22 g/min. The specifiedamount 1365 g of the enteric film coating liquid had been sprayed.

Enteric Film Coating Liquid (a):

Eudragit L30D-55 1017.3 g Eudragit NE30D 113.3 g Polyethylene glycol6000 34.0 g Glyceryl monostearate 20.0 g Polysorbate 80 6.0 g Ferricoxide 0.2 g Ferric oxide (yellow) 0.2 g Citric acid anhydrous 0.4 gPurified water 1410.8 g

Following this, with the inlet air temperature and the temperature ofthe loading being controlled at 76° C. and about 41° C., respectively,an enteric film coating liquid (B) of the following composition preparedin advance was sprayed in accordance with the tangential spray method ata spray rate of 22 g/min. The specified amount 5040 g of the entericfilm coating liquid had been sprayed.

Enteric Film Coating Liquid (B):

Eudragit L30D-55 3360 g Eudragit NE30D 373.2 g Triethyl citrate 224.4 gGlyceryl monostearate 72.0 g Polysorbate 80 21.6 g Ferric oxide 0.72 gFerric oxide (yellow) 0.72 g Citric acid anhydrous 0.6 g Purified water1706.8 g

Following this, with the inlet air temperature and the temperature ofthe loading being controlled at 80° C. and about 42° C., respectively,an enteric film coating liquid (A) of the above mentioned compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 21 g/min. The specified amount 682.5 g of theenteric film coating liquid had been sprayed.

(4) Production of Enteric Coated and Mannitol Coated Granules Having aCore

Following (3), with the inlet air temperature and the temperature of theloading being controlled at 80° C. and about 36° C., respectively, anfilm coating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 22 g/min. using a centrifugal fluidized coating granulator[manufactured by Powrex Corp. (Japan), MP-10 (Type 2)]. The sprayingoperation was stopped when the specified amount 735 g of the filmcoating liquid had been sprayed, and then drying was carried out in thegranulator for 10 minutes. The resulting granules were sieved through a#35 circular sieve (420 μm) and a #60 circular sieve (250 μm) to provide2319.5 g of enteric coated and mannitol coated granules having a core.

The average particle diameter of the obtained granules was 392.7 μm.

Film Coating Liquid:

Mannitol 100 g Purified water 600 g

(5) Production of Mixed Powders

To 270 g of the above enteric coated and mannitol coated granules havinga core were added 204.0 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

(6) Production of Orally Disintegrable Tablets

570 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch having abeveled edge, 12 mm in diameter, at a tabletting pressure of 1.5ton/cm², to provide tablets each weighing 570 mg.

The hardness and oral disintegration time of each tablet thus obtainedwere 3.7 kg and 35 seconds, respectively.

The acid-resistance of the obtained tablet was 3.4%.

Example 9 (1) Production of Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 300 g of Nonpareil 105(70-140) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 85°C. and about 28° C. respectively, the Nonpareil was coated by spraying abulk liquid of the following composition prepared in advance inaccordance with the tangential spray method at a spray rate of 20 g/min.The spraying operation was stopped when the specified amount of the bulkliquid had been sprayed, and then drying was carried out in thegranulator for 7 minutes. The resulting granules were sieved through a#48 circular sieve (300 μm) and a #100 circular sieve (150 μm) toprovide 757 g of granules having a core.

Bulk Liquid:

Lansoprazole 300 g Magnesium carbonate 100 g L-HPC  50 g HPC (Type SSL)100 g Water 1650 g 

(2) Production of Film-Undercoated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 680 g of the above granuleshaving a core. With the inlet air temperature and the temperature of theloading being controlled at 70° C. and about 36° C., respectively, anundercoating liquid of the following composition prepared in advance wassprayed in accordance with the tangential spray method at a spray rateof 10 g/min. to provide 672 g of film-undercoated granules having acore.

Undercoating Liquid:

HPMC  32 g (Type 2910, viscosity: 3 centistokes) Talc  8 g Water 760 g

(3) Production of Enteric Coated Granules Having a Core

A centrifugal fluidized coating granulator [manufactured by Powrex Corp.(Japan), MP-10 (Type 2)] was charged with 450 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 65° C. and about36° C., respectively, an enteric film coating liquid of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 17 g/min. The coated powderswere dried in vacuum at 40° C. for 16 hours, and sieved through a #42circular sieve (355 μm) and a #80 circular sieve (177 μm) to provide 950g of enteric coated granules having a core.

The average particle diameter of the obtained granules was 285.4 μm.

Enteric Film Coating Liquid:

Eudragit L30D-55 1078.3 g Eudragit NE30D 138.5 g Triethyl citrate 46.0 gGlyceryl monostearate 16.5 g Talc 16.0 g Polysorbate 80 9.0 g Iron oxide0.5 g Water 2038.5 g Sieve weight ratio #18 (850 μm) on 0% #30 (500 μm)on 0% #200 (75 μm) on 100% #200 (75 μm) pass 0%

(4) Production of Granulated Powders

A fluidized bed granulator [manufactured by Powrex Corp. (Japan), LAB-1]was charged with 1321.2 g of erythritol [manufactured by Nikken ChemicalCo., Ltd. (Japan)], 360.0 g of low-substituted hydroxypropyl celluloseLH-32 [hydroxypropoxyl group contents of 8.8%, manufactured by Shin-EtsuChemical Co., Ltd. (Japan)], 18.0 g of citric acid anhydrous, and 1.8 gof aspartame, and granulation was carried out while spraying a solutionwhich was prepared by dissolving 3.6 g of polyethylene glycol (PEG-6000)in 896.4 ml of purified water. The granules were dried to providegranulated powders. To the granulated powders were added 90.0 g ofcrospovidone and 5.4 g of magnesium stearate, which was admixed in a bagto give mixed powders.

(5) Production of Orally Disintegrable Tablets

200.0 g of the above enteric coated granules having a core and 300.0 gof the above mixed powders were tabletted using Autograph (trade name;compressing force measurement apparatus) with a punch having a bevelededge, 11 mm in diameter, at a tabletting pressure of 1.0 ton/cm², toprovide tablets each weighing 500 mg.

The hardness, the oral disintegration time and remaining ratio afteracid-resistance test of each tablet thus obtained were 4.2 kg, 27seconds and 96.3%, respectively.

INDUSTRIAL APPLICABILITY

The orally disintegrable tablet of the present invention has superiordisintegrability or dissolution so that it can be used for treatment orprevention of various diseases, as an orally disintegrable tabletcapable of being administered to the aged or children and easilyadministered without water. Also, because the orally disintegrabletablet of the present invention contains fine granules having theaverage particle diameter and an enteric coating layer such that it willnot impart roughness in mouth, it can be administered easily withoutdiscomfort at the administration and has superior acid-resistance.

Further, because the orally disintegrable tablet of the presentinvention has a suitable strength such that it will not be substantiallydamaged through production processes or circulation processes, it issuperior in stability for long-term storage and easy of use at theadministration.

Further, because the fine granule of the present invention ischaracterized in that it stably retains the acid-labile physiologicallyactive substance, contains the physiologically active substance in highcontent, be small and has superior stability, it can by used forproducing various compact pharmaceutical preparations such as tablets,capsules, suspensions and so forth. Such preparations are easy of use atthe administration. In addition, the fine granule of the presentinvention has superior acid-resistance after compression.

1. An orally disintegrable tablet which comprises (i) fine granuleshaving an average particle diameter of 400 μm or less, which finegranules comprise a composition coated by an enteric coating layer, saidcomposition having 10 weight % or more of an acid-labile physiologicallyactive substance and (ii) an additive.
 2. An orally disintegrable tabletof claim 1, wherein the average particle diameter of the fine granulesis 300 to 400 μm.
 3. An orally disintegrable tablet of claim 1, whereinthe fine granules further comprise a basic inorganic salt.
 4. An orallydisintegrable tablet of claim 1, wherein the additive comprises awater-soluble sugar alcohol.
 5. An orally disintegrable tablet of claim1, wherein the composition coated by an enteric coating layer is furthercoated by a coating layer which comprises a water-soluble sugar alcohol.6. An orally disintegrable tablet of claim 4, wherein the additivecomprises (i) crystalline cellulose and/or (ii) low-substitutedhydroxypropyl cellulose.
 7. An orally disintegrable tablet of claim 1,wherein the particle diameter of the fine granules is practically 425 μmor less.
 8. An orally disintegrable tablet of claim 1, wherein theparticle diameter of the fine granules is practically 400 μm or less. 9.An orally disintegrable tablet of claim 1, wherein the acid-labilephysiologically active substance is a benzimidazole compound or a saltthereof.
 10. An orally disintegrable tablet of claim 9, wherein thebenzimidazole compound is lansoprazole.
 11. An orally disintegrabletablet of claim 3, wherein the basic inorganic salt is a salt ofmagnesium and/or a salt of calcium.
 12. An orally disintegrable tabletof claim 1, wherein the composition comprises a core being coated by abenzimidazole compound and a basic inorganic salt, said core comprisingcrystalline cellulose and lactose.
 13. An orally disintegrable tablet ofclaim 12, wherein the core comprises 50 weight or more of lactose. 14.An orally disintegrable tablet of claim 12, wherein the core comprises40 to 50 weight % of crystalline cellulose and 50 to 60 weight % oflactose.
 15. An orally disintegrable tablet of claim 1, wherein thecomposition comprises 20 weight % or more of an acid-labilephysiologically active substance.
 16. An orally disintegrable tablet ofclaim 1, wherein the composition comprises 20 to 50 weight % of anacid-labile physiologically active substance.
 17. An orallydisintegrable tablet of claim 1, wherein the fine granules are producedby fluidized-bed granulation method.
 18. An orally disintegrable tabletof claim 1, wherein the enteric coating layer comprises an aqueousenteric polymer agent.
 19. An orally disintegrable tablet of claim 18,wherein the aqueous enteric polymer agent is a methacrylate copolymer.20. An orally disintegrable tablet of claim 18, wherein the entericcoating layer further comprises a sustained-release agent.
 21. An orallydisintegrable tablet of claim 20, wherein the sustained-release agent isa methacrylate copolymer.
 22. An orally disintegrable tablet of claim20, wherein the sustained-release agent is in an amount of 5 to 15weight % relative to 100 weight % of the aqueous enteric polymer agent.23. An orally disintegrable tablet of claim 4, wherein the water-solublesugar alcohol is erythritol.
 24. An orally disintegrable tablet of claim4, wherein the water-soluble sugar alcohol is mannitol.
 25. An orallydisintegrable tablet of claim 5, wherein the water-soluble sugar alcoholis in an amount of 5 to 97 weight % relative to 100 weight % of theorally disintegrable tablet apart from the fine granules.
 26. An orallydisintegrable tablet of claim 4, wherein the crystalline cellulose is inan amount of 3 to 50 weight relative to 100 weight % of the tablet apartfrom the fine granule.
 27. An orally disintegrable tablet of claim 6,wherein the content of hydroxypropoxyl group in the low-substitutedhydroxypropyl cellulose is 7.0 to 9.9 weight %.
 28. An orallydisintegrable tablet of claim 6, wherein the content of hydroxypropoxylgroup in the low-substituted hydroxypropyl cellulose is 5.0 to 7.0weight %.
 29. An orally disintegrable tablet of claim 1, which furthercomprises crospovidone.
 30. An orally disintegrable tablet of claim 1,wherein the oral disintegration time is one minute or less.
 31. Anorally disintegrable tablet of claim 1, which comprises no lubricantinside the tablet.
 32. Fine granules having an average particle diameterof 400 μm or less, which comprise a composition coated by an entericcoating layer, said composition having (i) 25 weight % or more of anacid-labile physiologically active substance and (ii) a basic inorganicsalt.
 33. Fine granules of claim 32, wherein the average particlediameter of the fine granules is 300 to 400 μm.
 34. Fine granules ofclaim 32, wherein the particle diameter of the fine granules ispractically 425 μm or less.
 35. Fine granules of claim 32, wherein theparticle diameter of the fine granules is practically 400 μm or less.36. Fine granules of claim 32, wherein the acid-labile physiologicallyactive substance is a benzimidazole compound or a salt thereof.
 37. Finegranules of claim 36, wherein the benzimidazole compound islansoprazole.
 38. Fine granules of claim 32, wherein the basic inorganicsalt is a salt of magnesium and/or a salt of calcium.
 39. Fine granulesof claim 32, wherein the composition comprises a core being coated by abenzimidazole compound and a basic inorganic salt, said core comprisingcrystalline cellulose and lactose.
 40. Fine granules of claim 39,wherein the core comprises 50 weight % or more of lactose.
 41. Finegranules of claim 32, wherein the composition comprises 25 to 40 weight% of an acid-labile physiologically active substance.
 42. Fine granulesof claim 32, which are produced by fluidized-bed granulation method. 43.Fine granules of claim 32, wherein the enteric coating layer comprisesan aqueous enteric polymer agent.
 44. Fine granules of claim 43, whereinthe aqueous enteric polymer agent is a methacrylate copolymer.
 45. Finegranules of claim 43, wherein the enteric coating layer further comprisea sustained-release agent.
 46. Fine granules of claim 45, wherein thesustained-release agent is a methacrylate copolymer.
 47. Fine granulesof claim 45, wherein the sustained-release agent is in an amount of 5 to15 weight % relative to 100 weight % of the aqueous enteric polymeragent.
 48. Fine granules of claim 32, wherein the enteric coating layeris in an amount of 50 to 70 weight % relative to 100 weight % of thefine granules.
 49. A tablet, granule, fine granule, capsule,effervescent or suspension preparation which comprises the fine granulesof claim 32.